METHOTREXATE, METHOTREXATE SODIUM

Chemistry - A folic acid antagonist, methotrexate is available commercially as the sodium salt. Itoccurs as a yellow powder that is soluble in water. Methotrexate sodium injection has a pH of 7.5-9. Methotrexate may also be known as Amethoptrin or MTX.

Storage, Stability, Compatibility

Methotrexate sodium tablets should be stored at room temperature (15-30°C) in well-closed containers and protected from light. The injection and powder forinjection should be stored at room temperature (15-30°C) and protected from light.
Methotrexate sodium is reportedly compatible with the following intravenous solutions anddrugs: Amino acids 4.25%/dextrose 25%, D5W, sodium bicarbonate 0.05 M, cephalothin sodium, cytarabine, 6-mercaptopurine sodium, sodium bicarbonate, and vincristine sulfate. In syringes, methotrexate is compatible with: bleomycin sulfate, cyclophosphamide, doxorubicin HCl, fluorouracil, furosemide, leucovorin calcium, mitomycin, vinblastine sulfate, and vincristine sulfate.
Methotrexate sodium compatibility information conflicts or is dependent on diluent or concentration factors with the following drugs or solutions: heparin sodium and metoclopramide HCl.
Compatibility is dependent upon factors such as pH, concentration, temperature and diluents used.
It is suggested to consult specialized references for more specific information (e.g., Handbook on
Injectable Drugs by Trissel; see bibliography).
Methotrexate sodium is reportedly incompatible with the following solutions or drugs:bleomycin sulfate (as an IV additive only; compatible in syringes and Y-lines), fluorouracil (as an IV additive only; compatible in syringes and Y-lines), prednisolone sodium phosphate, droperidoland ranitidine HCl.

Pharmacology - METHOTREXATE, METHOTREXATE SODIUM

An S-phase specific antimetabolite antineoplastic agent, methotrexate competitively inhibits folic acid reductase, thereby inhibiting the reduction of dihydrofolate to tetrahydrofolate and affecting production of purines and pyrimidines. Rapidly proliferating cells (e.g., neoplasms, bone marrow, GI tract epithelium, fetal cells, etc.) are most sensitive to the drug's effects.
Dihydrofolate reductase has a much greater affinity for methotrexate than either folic acid ordihydrofolic acid and coadministration of folic acid will not reduce methotrexate's effects.
Leucovorin calcium, a derivative of tetrahydrofolic acid, can block the effects of methotrexate.
Methotrexate also has immunosuppressive activity, possibly due to its effects on lymphocytereplication. Tumor cells have been noted to develop resistance to methotrexate which may be due todecreased cellular uptake of the drug.

Uses, Indications

Indicated for lymphomas and some solid tumors in dogs and cats (see the
Doses section and the recommended treatment protocol references at the end of this section). Inhuman medicine, methotrexate is also being used to treat refractory rheumatoid arthritis and severepsoriasis.

Pharmacokinetics - METHOTREXATE, METHOTREXATE SODIUM

Methotrexate is well absorbed from the GI tract after oral administration ofdosages <30 mg/m2 with a bioavailability of about 60%. In humans, peak levels occur within 4hours after oral dosing, and between 30 minutes and 2 hours after IM injection.
Methotrexate is widely distributed in the body and is actively transported across cel membranes.
Highest concentrations are found in the kidneys, spleen, gallbladder, liver and skin. When givenorally or parenterally, methotrexate does not reach therapeutic levels in the CSF. When givenintrathecally, methotrexate attains therapeutic levels in the CSF and also passes into the systemiccirculation. Methotrexate is about 50% bound to plasma proteins and crosses the placenta.
Methotrexate is excreted almost entirely by the kidneys via both glomerular filtration and activetransport. Serum half-lives are less than 10 hours and generally between 2-4 hours.

Contraindications, Precautions, Reproductive Safety

Methotrexate is contraindicated in patients with preexisting bone marrow depression, severe hepatic or renal insufficiency, or hypersensitive to the drug. It should be used with caution in patients who are susceptible to, or who havepreexisting signs or symptoms associated with, the adverse reactions associated with this drug.
When administering MTX, either wear gloves or immediately wash hands after handling. Glovesare particularly important if handling split, broken or crushed tablets. Preparation of intravenoussolutions should ideally be performed in a vertical laminar flow hood.
Methotrexate is teratogenic, embryotoxic and may affect spermatogenesis in male animals.

Adverse Effects, Warnings

In dogs and cats, gastrointestinal side effects are most prevalent withdiarrhea, nausea, and vomiting seen. Higher dosages may lead to listlessness, GI toxicity (ulcers, mucosal sloughing, stomatitis), hematopoietic toxicity (nadir at 4-6 days), hepatopathy, renal tubularnecrosis, alopecia, depigmentation, pulmonary infiltrates and fibrosis. CNS toxicity(encephalopathy) may be noted if methotrexate is given intrathecally. Rarely, anaphylaxis may beseen.

Overdosage, Acute Toxicity

Acute overdosage in dogs is associated with exacerbations of theadverse effects outlined above, particularly myelosuppression and acute renal failure. Acute tubularnecrosis is secondary to drug precipitation in the tubules. In dogs, the maximally tolerated dose isreported to be 0.12 mg/kg q24h for 5 days.
Treatment of acute oral overdoses include, emptying the gut and preventing absorption usingstandard protocols if the ingestion is recent. Additionally, oral neomycin has been suggested to helpprevent absorption of MTX from the intestine. In order to minimize renal damage, forced alkalinediuresis should be considered. Urine pH should be maintained between 7.5 and 8 by the addition of0.5 -1 mEq/kg of sodium bicarbonate per 500 ml of IV fluid.
Leucovorin calcium is specific therapy for methotrexate overdoses. It should be given as soon aspossible, preferably within the first hour and definitely within 48 hours. Doses of leucovorinrequired are dependent on the MTX serum concentration. Humans having serum concentrationsgreater than 5 x 10-7 M at 48 hours are likely to develop severe toxicity. Leucovorin in dosesranging from 25-200 mg/m2 every 6 hours doses is given until serum levels fall below 1 x 10-8 M.
Dogs treated with leucovorin at 15 mg/m2 every 3 hours IV for 8 doses, then IM q6h for 8 doseswere able to tolerate MTX doses as high as 3 g/m2 (O'Keefe and Harris 1990). Another dose of 3mg/m2 for leucovorin in dogs has also been suggested (Coppoc 1988).

Drug Interactions

Highly protein-bound drugs such as salicylates, sulfonamides, phenytoin, phenylbutazone, oral anticoagulants, tetracycline and chloramphenicol may displace MTXor be displaced by MTX from plasma proteins with resultant increased blood levels and toxicity ofboth drugs.
In humans, severe hematologic and GI toxicity has resulted in patients receiving both MTX andnon-steroidal antiinflammatory agents. Therefore, it is recommended not to use agents such asflunixin, naproxen, or meclofenamic acid in dogs also on MTX.
Salicylates or probenicid may inhibit the tubular secretion of MTX and increase its half life.
It has been suggested that folic acid supplements can inhibit the response to MTX, but this hasneither been confirmed nor refuted.
Pyrimethamine, a similar folic acid antagonist, may increase MTX toxicity and should not begiven to patients receiving MTX.
Oral neomycin may decrease the absorption of oral methotrexate if given concomitantly.
Drug/Laboratory Interactions - Methotrexate may interfere with the microbiologic assay forfolic acid.